Multiple sclerosis (MS) is a devastating illness without an effective treatment. Immune- mediated neuronal injury is a major factor in determining the extent of brain injury and loss of function. Based on animal studies with experimental allergic encephalomyelitis (EAE), key final common pathways of immune-mediated neuronal injury include the expression of the inducible nitric oxide (NO) synthase (iNOS), overproduction of NO and production of the toxic oxidant, peroxynitrite. Inotek, Inc has developed a revolutionary immunosuppressive agent, mercaptoethylguanidine (MEG), which interferes with several inflammatory pathways simultaneously, acting as a potent scavenger of peroxynitrite, and selective inhibitor of the inducible nitric oxide synthase. The specific aim of this phase 1 SBIR proposal is to establish whether MEG prevents the development of neurological deficits in murine models of EAE. This hypothesis will be tested using three different well established mouse models of EAE. Demonstration that MEG prevents tissue injury and reduces neuronal inflammation in this model would represent a breakthrough in the design of novel immunosuppressive regimens for MS and would justify continued commercial development of MEG. Phase 11 SBIR funding would be used to support pre-clinical toxicology/pathology and Phase 1 clinical studies. PROPOSED COMMERCIAL APPLICATION: Multiple sclerosis is a devastating unmet need. An effective therapy would have significant market penetration and result in annual US revenues of $100 million.